Which of the following is true regarding schizophrenia treatment and outcomes?

Practice Essentials

Schizophrenia is a brain disorder that affects how people think, feel, and perceive. The hallmark symptom of schizophrenia is psychosis, such as experiencing auditory hallucinations (voices) and delusions (fixed false beliefs).

Signs and symptoms

The symptoms of schizophrenia may be divided into the following 4 domains:

• Positive symptoms - Psychotic symptoms, such as hallucinations, which are usually auditory; delusions; and disorganized speech and behavior

• Negative symptoms - Decrease in emotional range, poverty of speech, and loss of interests and drive; the person with schizophrenia has tremendous inertia

• Cognitive symptoms - Neurocognitive deficits (eg, deficits in working memory and attention and in executive functions, such as the ability to organize and abstract); patients also find it difficult to understand nuances and subtleties of interpersonal cues and relationships

• Mood symptoms - Patients often seem cheerful or sad in a way that is difficult to understand; they often are depressed

See Clinical Presentation for more detail.

Diagnosis

Schizophrenia is not associated with any characteristic laboratory results.

Diagnostic criteria

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), to meet the criteria for diagnosis of schizophrenia, the patient must have experienced at least 2 of the following symptoms [1] :

• Delusions

• Hallucinations

• Disorganized speech

• Disorganized or catatonic behavior

• Negative symptoms

At least 1 of the symptoms must be the presence of delusions, hallucinations, or disorganized speech.

Continuous signs of the disturbance must persist for at least 6 months, during which the patient must experience at least 1 month of active symptoms (or less if successfully treated), with social or occupational deterioration problems occurring over a significant amount of time. These problems must not be attributable to another condition.

The American Psychiatric Association (APA) removed schizophrenia subtypes from the DSM-5 because they did not appear to be helpful for providing better-targeted treatment or predicting treatment response.

See Workup for more detail.

Management

Antipsychotic medications diminish the positive symptoms of schizophrenia and prevent relapses.

There is no clear antipsychotic drug of choice for schizophrenia. Clozapine is the most effective medication but is not recommended as first-line therapy.

Psychosocial treatment is essential. The best-studied psychosocial treatments are social skills training, cognitive-behavioral therapy, cognitive remediation, and social cognition training.

Psychosocial treatments are currently oriented according to the recovery model. According to this model, the goals of treatment for a person with schizophrenia are as follows:

• To have few or stable symptoms

• Not to be hospitalized

• To manage his or her own funds and medications

• To be either working or in school at least half-time

See Treatment and Medication for more detail.

Background

Schizophrenia is a brain disorder that probably comprises multiple etiologies. The hallmark symptom of schizophrenia is psychosis, such as experiencing auditory hallucinations (voices) and delusions (fixed false beliefs). Impaired cognition or a disturbance in information processing is an underappreciated symptom that interferes with day-to-day life. People with schizophrenia have lower rates of employment, marriage, and independent living compared with other people.

Schizophrenia is a clinical diagnosis. It must be differentiated from other psychiatric and medical illnesses, as well as from disorders such as heavy metal toxicity, adverse effects of drugs, and vitamin deficiencies. (See DDx and Workup.)

Treatment of schizophrenia requires an integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and is best carried out by a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment.

Antipsychotic medications, also known as neuroleptic medications or major tranquilizers, diminish the positive symptoms of schizophrenia and prevent relapses. Unfortunately, they are also associated with a number of adverse effects. (See Treatment and Medication.)

Diagnostic criteria (DSM-5)

The specific DSM-5 criteria for schizophrenia are as follows [1] :

• The presence of 2 (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated), with at least 1 of them being (1), (2), or (3): (1) delusions, (2) hallucinations, (3) disorganized speech, (4) grossly disorganized or catatonic behavior, and (5) negative symptoms

• For a significant portion of the time since the onset of the disturbance, level of functioning in 1 or more major areas (eg, work, interpersonal relations, or self-care) is markedly below the level achieved before onset; when the onset is in childhood or adolescence, the expected level of interpersonal, academic or occupational functioning is not achieved

• Continuous signs of the disturbance persist for a period of at least 6 months, which must include at least 1 month of symptoms (or less if successfully treated); prodromal symptoms often precede the active phase, and residual symptoms may follow it, characterized by mild or subthreshold forms of hallucinations or delusions

• Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms or (2) any mood episodes that have occurred during active-phase symptoms have been present for a minority of the total duration of the active and residual periods of the illness

• The disturbance is not attributable to the physiologic effects of a substance (eg, a drug of abuse or a medication) or another medical condition

• If there is a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms or schizophrenia are also present for at least 1 month (or less if successfully treated)

In addition to the 5 symptom domain areas identified in the first diagnostic criterion, assessment of cognition, depression, and mania symptom domains is vital for distinguishing between schizophrenia and other psychotic disorders.

Various course specifiers are used, though only if the disorder has been present for at least 1 year and if they do not contradict diagnostic course criteria. These specifiers include the following [1] :

• First episode, currently in acute episode

• First episode, currently in partial remission

• First episode, currently in full remission

• Multiple episodes, currently in acute episode

• Multiple episodes, currently in partial remission

• Multiple episodes, currently in full remission

• Continuous

• Unspecified

The presence or absence of catatonia is specified. Individuals meeting the criteria for catatonia receive an additional diagnosis of catatonia associated with schizophrenia to indicate the presence of the comorbidity.

Finally, the current severity of the disorder is specified by evaluating the primary symptoms of psychosis and rating their severity on a 5-point scale ranging from 0 (not present) to 4 (present and severe).

Schizophrenia subtypes were removed from DSM-5 because they did not appear to help with providing better-targeted treatment or predicting treatment response.

Pathophysiology

Anatomic, neurotransmitter, and immune system abnormalities have been implicated in the pathophysiology of schizophrenia.

Anatomic abnormalities

Neuroimaging studies show differences between the brains of those with schizophrenia and those without this disorder. For example, the ventricles are somewhat larger, there is decreased brain volume in medial temporal areas, and changes are seen in the hippocampus. [2, 3, 4]

Interest has also focused on the various connections within the brain rather than on localization in a single part of the brain. Magnetic resonance imaging (MRI) studies show anatomic abnormalities in a network of neocortical and limbic regions and interconnecting white-matter tracts. [5] A meta-analysis of studies using diffusion tensor imaging (DTI) to examine white matter found that 2 networks of white-matter tracts are reduced in schizophrenia. [6]

In the Edinburgh High-Risk Study, brain imaging showed reductions in whole-brain volume and in left and right prefrontal and temporal lobe volumes in 17 of 146 people who were at high genetic risk for schizophrenia. The changes in prefrontal lobes were associated with increasing severity of psychotic symptoms. [7]

In a meta-analysis of 27 longitudinal MRI studies comparing schizophrenic patients with control subjects, schizophrenia was associated with structural brain abnormalities that progressed over time. The abnormalities identified included loss of whole-brain volume in both gray and white matter and increases in lateral ventricular volume. [8]

These findings are of interest more for research purposes than for clinical application.

Neurotransmitter system abnormalities

Abnormalities of the dopaminergic system are thought to exist in schizophrenia. The first clearly effective antipsychotic drugs, chlorpromazine and reserpine, were structurally different from each other, but they shared antidopaminergic properties. Drugs that diminish the firing rates of mesolimbic dopamine D2 neurons are antipsychotic, and drugs that stimulate these neurons (eg, amphetamines) exacerbate psychotic symptoms.

Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, and hyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may coexist. (Negative and positive symptoms are defined elsewhere; see Presentation.) Moreover, the newer antipsychotic drugs block both dopamine D2 and serotonin (5-hydroxytryptamine [5-HT]) receptors.

Clozapine, perhaps the most effective antipsychotic agent, is a particularly weak dopamine D2 antagonist. Thus, other neurotransmitter systems, such as norepinephrine, serotonin, and gamma-aminobutyric acid (GABA), are undoubtedly involved.

Much research focuses on the N -methyl-D-aspartate (NMDA) subclass of glutamate receptors because NMDA antagonists, such as phencyclidine and ketamine, can lead to psychotic symptoms in healthy subjects. [9, 10] Some researchers consider schizophrenia, in large part, a hypoglutamatergic disorder.

Inflammation and immune function

Immune function is disturbed in schizophrenia. [11] Overactivation of the immune system (eg, from prenatal infection or postnatal stress) may result in overexpression of inflammatory cytokines and subsequent alteration of brain structure and function. For example, schizophrenic patients have elevated levels of proinflammatory cytokines that activate the kynurenine pathway, by which tryptophan is metabolized into kynurenic and quinolinic acids; these acids regulate NMDA receptor activity and may also be involved in dopamine regulation.

Insulin resistance and metabolic disturbances, which are common in the schizophrenic population, have also been linked to inflammation. Thus, inflammation might be related both to the psychopathology of schizophrenia and to metabolic disturbances seen in patients with schizophrenia. [12]

Etiology

The causes of schizophrenia are not known. Most likely, there are at least 2 sets of risk factors, genetic and perinatal. In addition, undefined socioenvironmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities. [13, 14, 15] Increased paternal age is associated with a greater risk of schizophrenia.

Genetic factors

The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but not in adopted relatives. [16] The risk of schizophrenia in first-degree relatives of persons with schizophrenia is 10%. If both parents have schizophrenia, the risk of schizophrenia in their child is 40%. Concordance for schizophrenia is about 10% for dizygotic twins and 40-50% for monozygotic twins.

Genome-wide association studies have identified many candidate genes, but the individual gene variants that have been implicated so far account for only a small fraction of schizophrenia cases, and these findings have not always been replicated in different studies. The genes that have been found mostly change a gene’s expression or a protein’s function in a small way.

In 2021, Cheng et al investigated the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) to identify shared genomic loci. Based on GWAS data from 139,053 participants, the researchers found that most genetic variants associated with cortical SA and TH are also linked to the risk of developing schizophrenia. Results were obtained using MiXeR, a statistical tool that quantifies polygenic overlap irrespective of genetic correlation. MiXeR estimated schizophrenia to be more polygenic than total SA and average TH (9,703 single-nucleotide variants, or SNVs, vs. 2101 and 1,363, respectively). Most of the SNVs associated with total SA (93.6%) may be associated with the development of schizophrenia, according to the study. [17]

In a 2014 study, researchers identified new genetic loci not previously known to be associated with schizophrenia. Of the 108 genetic loci linked to schizophrenia that were identified in the study, 83 had not previously been found. The investigators also determined that among 128 independent associations related to the 108 loci, enriched associations existed not only among genes expressed in the brain, but also among those expressed in tissues related to immunity, giving support to the theory linking the immune system to schizophrenia. [18, 19]

Some loci of particular interest include the following:

• Catechol-O-methyltransferase (COMT) gene

• RELN gene

• Nitric oxide synthase 1 adaptor protein (NOS1AP) gene

• Metabotropic glutamate receptor 3 (GRM3) gene

The COMT gene codes for the postsynaptic intracellular enzyme COMT, which is involved in the methylation and degradation of the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. The several allelic variants of COMT affect its activity. The valine-valine variant degrades dopamine faster than the valine-methionine variant does; subjects with 2 copies of the methionine allele were less likely to develop psychotic symptoms with cannabis use than were other cannabis-using subjects without that variant. [20]

The RELN gene codes for the protein reelin, which plays a role in brain development and GABAergic activity. In an international study, a common variant in this gene increased the risk of schizophrenia, but only in women. [21]

The NOS1AP gene codes for the enzyme nitric oxide synthase, which is found in high concentration in inhibitory neurons in the brain. Nitric oxide acts as an intracellular messenger. Using a newly developed statistical technique, the posterior probability of linkage disequilibrium, researchers have identified a single-nucleotide polymorphism associated with higher levels of expression of this gene in postmortem brain samples from individuals with schizophrenia. [22]

The GRM3 gene is a protein-coding gene associated with bipolar affective disorder. In a 2014 study, researchers found a variant in the GRM3 gene that was associated with a two- to three-fold increase in the risk of developing schizophrenia or alcohol dependence and an approximately three-fold greater risk of developing bipolar disorder. In the study, researchers performed a genetic analysis of 4971 patients with schizophrenia, bipolar disorder, or alcoholism and of 1309 healthy controls. The GRM3 variant associated with schizophrenia, alcohol dependence, and bipolar disorder in the study, which is seen in about 1 of every 200 people, may be a nonspecific risk factor for mental disorders and a potential treatment target. [18, 23]

Other genetic changes involve the structure of the gene. For example, copy number variants are deletions and duplications of segments of DNA; they can involve genes or regulatory regions. These variants are usually inherited, but can arise spontaneously. Copy number variants such as the deletions found at 1q21.1, 15q13.3, and 22q11.2 increase the risk of developing schizophrenia. [24, 25] At most, however, these findings probably account for only a small part of the heritability of schizophrenia.

In addition, the effects of some of these copy number variants are not restricted to schizophrenia. Other copy number variant disorders include autism, intellectual disability, attention-deficit hyperactivity disorder, and epilepsy. [26]

In a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a copy number variant at 1 of the following loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2. Clinically, these people had various neurologic or psychiatric disorders, including developmental delay, intellectual disability, and autism-related disorders. Subjects also had congenital anomalies. [27]

Many studies have also looked for abnormalities in neurodevelopmental genes. Disruptions in the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been associated with schizophrenia, albeit with significant variability between studies. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40] These findings also lend support to the hypothesis that schizophrenia is a disease in which multiple rare genetic variants lead to a common clinical outcome.

Some people with schizophrenia have no family history of the disorder. These cases may be the result of new mutations. De novo mutations in the exome (the part of the chromosome that codes for proteins) seem to be more common in patients with schizophrenia than would otherwise be expected. [41, 42] In a pair of exome sequencing studies, researchers identified de novo genetic mutations in patients with schizophrenia that cluster in specific proteins involved in brain function and overlap with mutations that have been identified in patients with autism, mental retardation and intellectual disability. [43, 44]

A genome-wide association study beginning with a Swedish sample of 5,000 cases and 6,000 controls compared the results with a previous genome-wide association study and findings of single-nucleotide polymorphisms (SNP) in independent examples. It found a clustering at 22 loci, 14 of which were new. Most of the SNPs were common and, collectively, could account for perhaps as much as one third of the variance in liability for schizophrenia. In other words, common genetic variation may be involved in schizophrenia. This is somewhat similar to the understanding of other complex trait diseases such as coronary artery disease. [45]

Schizophrenia and bipolar disorder are likely to have a large overlap in genetic risk factors, but only a small portion of this genetic risk has been identified. [46]

As can be seen, working out the details of these genetic factors is difficult. Interactions with the rest of the genome and with the environment will doubtless prove to be important. Nonetheless, a meta-analysis of twin studies estimated that genetic factors account for about four fifths of liability to schizophrenia. [47]

Perinatal factors

Women who are malnourished or who have certain viral illnesses during their pregnancy may be at greater risk of giving birth to children who later develop schizophrenia. [48] For example, children born to Dutch mothers who were malnourished during World War II have a high rate of schizophrenia.

After the 1957 influenza A2 epidemics in Japan, England, and Scandinavia, rates of schizophrenia were higher among offspring of women who contracted influenza during their second trimester. Women in California who were pregnant between 1959 and 1966 were more likely to have a child who developed schizophrenia if they had influenza in the first trimester of their pregnancy. [49]

Obstetric complications may be associated with a higher incidence of schizophrenia. Children born in the winter months may be at greater risk for developing schizophrenia. [50]

A study of Finnish women supported an interaction between genetic and environmental influences on causation of schizophrenia. [51] In this study, a review of 9596 women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection between 1947 and 1990 found no overall significant increase in the risk of schizophrenia among their offspring but a 5-fold higher risk among the offspring of women who also had a family history of psychosis. The authors estimated that among offspring of women with both prenatal pyelonephritis and a positive family history of psychotic disorders, 38-46% of schizophrenia cases resulted from the synergistic action of the 2 risk factors. [51]

Drug use

A new study suggests that heavy marijuana use in teenagers aged 15–17 years may hasten the onset of psychosis in those at high risk for developing a psychotic disorder. In an analysis of 247 hospitalized patients who had experienced first-episode psychosis, the Allied Cohort on the Early course of Schizophrenia (ACES) II project found that the onset of psychosis in those who used cannabis from age 15 to 17 years occurred at a mean age of 21.07 years, compared with a mean age of 23.86 years in patients who did not use cannabis during those same teenage years. However, the researchers could not say whether marijuana use may actually cause psychosis to develop early or whether people who have a predilection for earlier onset of psychosis also may be more likely, owing to various factors, to use marijuana. [52]

Epidemiology

United States and international statistics

The lifetime prevalence of schizophrenia has generally been estimated to be approximately 1% worldwide. [53] However, a systematic review by Saha et al of 188 studies drawn from 46 countries found a lifetime risk of 4.0 per 1000 population; prevalence estimates from countries considered least developed were significantly lower than those from countries classed as emerging or developed. [54] Immigrants to developed countries show increased rates of schizophrenia, with the risk extending to the second generation. [13, 14, 15]

Age-, race-, and sex-related demographics

The onset of schizophrenia usually occurs between the late teens and the mid-30s. [1] For males, the peak age of onset for the first psychotic episode is in the early to middle 20s; for females, it is in the late 20s. The first 5–10 years of the illness can be stormy, but this initial period is usually followed by decades of relative stability (though a return to baseline is unusual). Positive symptoms are more likely to remit than are cognitive and negative symptoms (see Presentation).

Although some variation by race or ethnicity has been reported, no racial differences in the prevalence of schizophrenia have been positively identified. Some research indicates that schizophrenia is diagnosed more frequently in black people than in white people; this finding has been attributed to cultural bias of practitioners.

The prevalence of schizophrenia is about the same in men and women. The onset of schizophrenia is later in women than in men, and the clinical manifestations are less severe. This may be because of the antidopaminergic influence of estrogen.

Prognosis

The prognosis is guarded. Full recovery is unusual. Early onset of illness, family history of schizophrenia, structural brain abnormalities, and prominent cognitive symptoms are associated with a poor prognosis. The prognosis is better for people living in low-income and middle-income countries. [55]

Symptoms usually follow a waxing-and-waning course and their nature may change over time. Positive symptoms respond fairly well to antipsychotic medication, but the other symptoms are quite persistent.

Because of vocational difficulties, many patients with schizophrenia also have to cope with the burdens of poverty. These include limited access to medical care, which may lead to poor control of the disease; homelessness; and incarceration, typically for minor offenses.

People with schizophrenia have a 5% lifetime risk of suicide. [56] Other factors that contribute to increased mortality include lifestyle issues such as cigarette smoking, poor nutrition, and lack of exercise, and perhaps poorer medical care and complications of medications. A study from Britain shows that this “mortality gap” is increasing. [57]

Women with schizophrenia may have higher rates of breast cancer than women in the general population. In a meta-analysis of more than 125,000 women, this increased risk was significant in studies in which breast cancer occurred before the diagnosis of schizophrenia was excluded. However, the association between schizophrenia and breast cancer incidence was not significant in studies that did not specify the exclusion of breast cancer cases that occurred prior to the diagnosis of schizophrenia. Researchers suggest factors such as obesity, nulliparity, and potentially even increased prolactin levels may raise the risk for breast cancer. It is important to note that significant heterogeneity exists among the included studies, and it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population. [58]

Patient Education

The nature of schizophrenia makes it a potentially difficult illness for patients to understand. Nevertheless, teaching the patient to understand the importance of medication compliance and of abstinence from alcohol and other drugs of abuse is important.

It is helpful to work with the patient so that both patient and family can learn to recognize early signs of a decompensation (eg, insomnia or increased irritability). A review of 44 studies showed that education of patients about the nature of their illness and treatment, when added to standard care, led to reductions in rehospitalization and symptoms. [59] Education may improve adherence to medication and may help the patient cope with the illness better in other ways.

Family members can be referred to the National Alliance on Mental Illness (NAMI) (or another appropriate support group, if one is available). These groups can provide education and support.

People with schizophrenia have also championed self-help recovery-based approaches to care, with an emphasis on developing the personal strengths and resilience needed to combat this illness.

Much psychosocial treatment that is discussed below has an educational component.

Because other illnesses are common in schizophrenia, education about the importance of a healthy lifestyle and regular health care is helpful. Counseling with respect to sexuality, pregnancy, and sexually transmitted diseases is important for these patients.

The following resources may also be helpful:

For patient education resources, see the Schizophrenia Health Center, as well as Schizophrenia.

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Author

Frances R Frankenburg, MD Professor, Department of Psychiatry, Boston University School of Medicine; Chief of Inpatient Psychiatry and Consulting Psychiatrist, Edith Nourse Rogers Memorial Veterans Administration Medical Center; Associate Psychiatrist, McLean Hospital

Frances R Frankenburg, MD is a member of the following medical societies: Alpha Omega Alpha, American Psychiatric Association

Disclosure: Nothing to disclose.

Chief Editor

Glen L Xiong, MD Associate Clinical Professor, Department of Psychiatry and Behavioral Sciences, Department of Internal Medicine, University of California, Davis, School of Medicine; Medical Director, Sacramento County Mental Health Treatment Center

Glen L Xiong, MD is a member of the following medical societies: AMDA - The Society for Post-Acute and Long-Term Care Medicine, American College of Physicians, American Psychiatric Association, Central California Psychiatric Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SafelyYou, Blue Cross Blue Shield, Included Health<br/>book co-editor for: Wolter Kluwer, American Psychiatric Publishing Inc.

Acknowledgements

Ronald C Albucher, MD Chief Medical Officer, Westside Community Services; Consulting Staff, California Pacific Medical Center

Ronald C Albucher, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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